Lymphomas are a heterogeneous group of malignancies that are primarily divided into Hodgkin and non- Hodgkin lymphomas (NHL), with B cell lymphomas representing the majority of NHL. The Surveillance, Epidemiology and End Results (SEER) database shows that unlike other cancers, the incidence of NHL is rising. NHL is currently the sixth and fifth most common malignancy diagnosed in men and women, respectively in the US. Natural killer T (NKT) cells are important in regulating immune responses to tumors. The observation that lymphoma patients have a reduction in both NKT cell number and function suggests that in NHL the anti-tumor effects mediated by these cells may be compromised. The mechanism by which NKT cells are impaired in lymphoma patients has yet to be identified. In this proposal we are focusing on a specific type of NHL, Mantle Cell Lymphoma (MCL), for which there is currently no curative treatment option available. MCL is characterized by the chromosomal translocation and nuclear overexpression of cyclin D1. Secondary chromosomal abnormalities and dysregulation of cell cycle machinery also contribute to MCL pathogenesis, such as aberrant activation of phosphoinositide-3 kinase/Akt (PI3K/Akt) and mammalian target of rapamycin (mTOR) signaling. Two well-established targets of PI3K/Akt and mTOR signaling pathways are hypoxia- inducible factors (HIF) 1 and 2. In fact, overexpression of HIF-11 is associated with more aggressive disease in MCL patients. HIF-1 plays a role in the reprogramming of cancer metabolism by activating the transcription of genes encoding glucose transporters and glycolytic enzymes. In our preliminary data we have found that NKT cells can specifically recognize malignant B cells from MCL patients, compared to B cells isolated from healthy donors. As NKT cells are activated by glycolipid antigens, it is likely that overexpression of HIF-1 alters the repertoire of glycolipid antigens. Here we hypothesize that the overexpression of HIF-11 modulates CD1d- mediated NKT responses to MCL. We propose to test our hypothesis with in vitro studies using cell lines to identify the mechanism by which HIF-11 regulates NKT cell function, in vivo studies using a murine model of MCL to determine whether using pharmacologic inhibitors of HIF-11 signaling can restore NKT cell function, and ex vivo studies using clinical samples to discern whether the expression of HIF-11 correlates with the number and/or the function of NKT cells in the blood of lymphoma patients. These studies will provide a better understanding of NKT cell biology and their role in anticancer immunity. Collectively, this work will uniquely advance our understanding of the immune response during lymphoma progression and may lead to new therapeutic strategies. PUBLIC HEALTH RELEVANCE: Mantle cell lymphoma (MCL) is a subtype of non-Hodgkin's lymphoma, in which over 90% of patients are stage III-IV at diagnosis, and has a mean survival of less than 3 years following diagnosis. In this proposal, we are hypothesizing that one mechanism by which these tumors escape immune detection is through a loss of NKT cell function caused by alterations in cellular metabolism in malignant B cells. This work is important because could lead to the development of new therapeutic targets for the treatment of MCL.